Whole Genome Scan for Modifier Genes in Colorectal Cancer

全基因组扫描结直肠癌修饰基因

• 批准号: 7926367
• 负责人: LOIC LE MARCHAND
• 金额: $ 180.27万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926367
• 关键词: Admixture; Adopted; African American; Alcohols; Biological; Blood specimen; Calcium; Cancer Center; Characteristics; Clinical Data; Cohort Studies; Collaborations; Colon; Colorectal Cancer; Communities; Confidentiality; Consumption; CpG Island Methylator Phenotype; DNA; Data; Data Set; Defect; Development; Diagnostic; Disease; Environment; Environmental Risk Factor; Ethnic group; Folate; Funding; Gene-Modified; Genes; Genetic; Genetic Variation; Genome; Genome Scan; Genomics; Genotype; Genus Cola; Hand; Haplotypes; Hawaii; Hawaiian population; Heterogeneity; Incidence; Individual; Inherited; Institutes; Investments; Japan; Japanese American; Japanese Population; Large Intestine; Latino; Life Style; Link; Linkage Disequilibrium; Los Angeles; Malignant Neoplasms; Meat; Methods; Microsatellite Instability; Mismatch Repair; Modeling; Morbidity - disease rate; Mutation; Online Systems; Overnutrition; Participant; Pathway interactions; Play; Policies; Population; Population Genetics; Predisposition; Prevention; Primary Prevention; Public Health; Rectal Cancer; Relative (related person); Research; Research Personnel; Resources; Risk; Risk Assessment; Risk Factors; Role; Sampling; Screening procedure; Secure; Single Nucleotide Polymorphism; Smoking; Staging; Stratification; Surveys; Susceptibility Gene; Syndrome; Technology; Testing; Therapeutic; Tokyo; United States National Institutes of Health; Variant; Vitamin D; analytical method; base; beef; biobank; calcium intake; cancer genetics; cancer risk; cohort; data sharing; design; experience; gene environment interaction; genetic variant; genome wide association study; genome-wide; high risk; molecular phenotype; mortality; novel; novel therapeutic intervention; population based; public health relevance; racial and ethnic; racial/ethnic difference; sample collection; statistics; tumor

DESCRIPTION (provided by applicant): Common inherited DNA variants are expected to play an important role in colorectal cancer (CRC). However, the main effects for these variants are likely to be weak because as much as 75-80% of CRC cases are "explainable" by known or suspected lifestyle risk factors. Most importantly, recent evidence suggests that common genetic factors for CRC act by amplifying these environmental effects. It is now practical to comprehensively study association with inherited DNA variation genome-wide. We propose to build on existing collaborations to undertake such a study using a multiethnic cohort representing the diversity of the U.S. population and a Japanese cohort. We have established a large biorepository linked to detailed, pre-diagnostic lifestyle exposure information and clinical data for five racial-ethnic groups in the Multiethnic Cohort study (MEC), as well as for Japanese in Japan in the Japan Public Health Center cohort study (JPHC). We will perform a two-stage, well powered, population-based, genome-wide association study of CRC in the MEC and JPHC, concentrating on both main effects and gene-environment interactions. In Stage 1, we will test ~1 million single nucleotide polymorphisms (SNPs) for association with CRC in 1,000 cases and 1,000 controls of Japanese ancestry from the MEC and evaluate both the main effects of each SNP (overall and for colon and rectal cancers) and their interactions with a well-defined set of lifestyle variables (folate, red meat, alcohol and calcium intakes, and BMI and pack-years). About 16,000 of the most strongly associated variants (singly, by anatomical subsite, or interacting with these lifestyle risk factors) with risk will be further evaluated in Stage 2, using additional subjects, consisting of 3,000 CRC cases and 3,000 controls from the MEC (African Americans, Japanese Americans, Latinos, Native Hawaiians and Whites) and JPHC (Japanese). Significance and heterogeneity of effects will be assessed using a combined analysis of Stages 1 and 2. Data from this study will quickly be made available to the research community. The elucidation of modifying genes for CRC will identify new mechanistic pathways and generate a better biological understanding on which to base individual risk assessment and new therapeutic approaches. PUBLIC HEALTH RELEVANCE: This multiethnic study will interrogate the entire genome for association with inherited genetic variants that may increase risk of colorectal cancer, either independently or by amplifying the effects of specific lifestyle risk factors. The study will generate a better biological understanding of the disease on which to base new prevention and therapeutic approaches.

描述（由申请人提供）：常见的遗传DNA变异有望在结直肠癌（CRC）中发挥重要作用。然而，这些变异的主要影响可能很弱，因为多达75-80%的结直肠癌病例可以用已知或可疑的生活方式风险因素“解释”。最重要的是，最近的证据表明，CRC的共同遗传因素通过放大这些环境影响而起作用。在全基因组范围内全面研究与遗传DNA变异的关联已成为现实。我们建议在现有合作的基础上进行这样的研究，使用代表美国人口多样性的多民族队列和日本队列。我们已经建立了一个大型生物库，与多民族队列研究（MEC）中的五个种族-民族以及日本公共卫生中心队列研究（JPHC）中的日本人的详细诊断前生活方式暴露信息和临床数据相关联。我们将在MEC和JPHC中进行一项两阶段、基于人群的CRC全基因组关联研究，重点关注主要效应和基因-环境相互作用。在第一阶段，我们将在1000例病例和1000例来自MEC的日本血统的对照中测试约100万个单核苷酸多态性（SNP）与结直肠癌的关联，并评估每个SNP的主要影响（总体和结肠和直肠癌）及其与一组明确的生活方式变量（叶酸、红肉、酒精和钙摄入量、BMI和包年）的相互作用。在第二阶段，将使用额外的受试者，包括3000例结直肠癌病例和3000例来自MEC（非洲裔美国人、日裔美国人、拉丁美洲人、夏威夷原住民和白人）和JPHC（日本人）的对照，进一步评估大约16000例与风险最密切相关的变异（单个、通过解剖亚位点，或与这些生活方式风险因素相互作用）。效果的显著性和异质性将通过一期和二期的综合分析进行评估。这项研究的数据将很快提供给研究界。CRC修饰基因的阐明将识别新的机制途径，并产生更好的生物学理解，从而为个体风险评估和新的治疗方法奠定基础。公共卫生相关性：这项多种族研究将询问整个基因组与可能增加结直肠癌风险的遗传基因变异的关联，无论是独立的还是通过放大特定生活方式风险因素的影响。这项研究将对这种疾病产生更好的生物学认识，从而为新的预防和治疗方法奠定基础。